Methods and devices for inhibiting nerves when activating brown adipose tissue

ABSTRACT

Methods and devices are provided for inhibiting nerves when activating brown adipose tissue (BAT). In general, a first nerve type (e.g., sympathetic nerves) innervating BAT can be activated while at least one other nerve type (e.g., parasympathetic nerves and/or sensory nerves) innervating BAT is being suppressed. A first neuromodulator (e.g., an electrical signal, a chemical, a light, cooling, etc.) can be applied to activate the first nerve type, and a second neuromodulator can be applied to inhibit the at least one other nerve type. In this way, parasympathetic nerves and/or sensory nerves innervating BAT can be inhibited when activating sympathetic nerves innervating BAT.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. patent application Ser.No. 16/108,132 entitled “Methods And Devices For Inhibiting Nerves WhenActivating Brown Adipose Tissue” filed Aug. 22, 2018, which claimspriority to U.S. patent application Ser. No. 14/584,046, now U.S. Pat.No. 10,092,738, entitled “Methods And Devices For Inhibiting Nerves WhenActivating Brown Adipose Tissue” filed Dec. 29, 2014, which are herebyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods and devices for inhibitingnerves when activating brown adipose tissue.

BACKGROUND OF THE INVENTION

Obesity is becoming a growing concern, particularly in the UnitedStates, as the number of people with obesity continues to increase andmore is learned about the negative health effects of obesity. Severeobesity, in which a person is 100 pounds or more over ideal body weight,in particular poses significant risks for severe health problems.Accordingly, a great deal of attention is being focused on treatingobese patients.

Surgical procedures to treat severe obesity have included various formsof gastric and intestinal bypasses (stomach stapling), biliopancreaticdiversion, adjustable gastric banding, vertical banded gastroplasty,gastric plications, and sleeve gastrectomies (removal of all or aportion of the stomach). Such surgical procedures have increasingly beenperformed laparoscopically. Reduced postoperative recovery time,markedly decreased post-operative pain and wound infection, and improvedcosmetic outcome are well established benefits of laparoscopic surgery,derived mainly from the ability of laparoscopic surgeons to perform anoperation utilizing smaller incisions of the body cavity wall. However,such surgical procedures risk a variety of complications during surgery,pose undesirable post-operative consequences such as pain and cosmeticscarring, and often require lengthy periods of patient recovery.Patients with obesity thus rarely seek or accept surgical intervention,with only about 1% of patients with obesity being surgically treated forthis disorder. Furthermore, even if successfully performed and initialweight loss occurs, surgical intervention to treat obesity may notresult in lasting weight loss, thereby indicating a patient's need foradditional, different obesity treatment.

Nonsurgical procedures for treating obesity have also been developed.However, effective therapies for increasing energy expenditure and/oraltering a patient's metabolism, e.g., a basal metabolic rate, leadingto improvements in metabolic outcomes, e.g., weight loss, have focusedon pharmaceutical approaches, which have various technical andphysiological limitations.

It has been recognized in, for example, U.S. Pat. No. 6,645,229 filedDec. 20, 2000 and entitled “Slimming Device,” that brown adipose tissue(BAT) plays a role in the regulation of energy expenditure and thatstimulating BAT can result in patient slimming. BAT activation isregulated by the sympathetic nervous system and other physiological,e.g., hormonal and metabolic, influences. When activated, BAT removesfree fatty acids (FFA) and oxygen from the blood supply for thegeneration of heat. The oxidative phosphorylation cycle that occurs inthe mitochondria of activated BAT is shown in FIGS. 1 and 2.

Accordingly, there is a need for improved methods and devices fortreating obesity and in particular for activating BAT.

SUMMARY OF THE INVENTION

The present invention generally provides methods and devices forinhibiting nerves when activating brown adipose tissue. In oneembodiment, a medical method is provided that includes applying a firstneuromodulator to a depot of BAT. The application of the firstneuromodulator can cause activation of a first nerve type in the BAT soas to increase energy expenditure of the BAT. The method can alsoinclude applying a second neuromodulator to the depot of BATsimultaneously with the application of the first neuromodulator. Theapplication of the second neuromodulator can inhibit a second nerve typein the BAT that is different from the first nerve type.

The method can vary in any number of ways. For example, the first nervetype can include sympathetic nerves, and the second nerve type caninclude parasympathetic nerves. For another example, the first nervetype can include sympathetic nerves, and the second nerve type caninclude sensory nerves. For still another example, the application ofthe second neuromodulator can start before the application of the firstneuromodulator begins so as to start inhibiting the second nerve typebefore the first nerve type is activated. For yet another example, thefirst neuromodulator can include applying a first electrical signal tothe depot of BAT, and applying the second neuromodulator can includeapplying a second electrical signal to the depot of BAT that isdifferent from the first electrical signal. For another example,applying one of the first and second neuromodulators can includeapplying an electrical signal to the depot of BAT, and applying theother of the second neuromodulators can include delivering a chemical tothe depot of BAT. For still another example, applying the firstneuromodulator can include delivering a first chemical to the depot ofBAT, and applying the second neuromodulator can include delivering asecond chemical to the depot of BAT that is different from the firstchemical. For another example, applying the first neuromodulator caninclude at least one of applying an electrical signal to the depot ofBAT, delivering a chemical to the depot of BAT, cooling the depot ofBAT, and applying a light to the depot of BAT, and applying the secondneuromodulator can include at least one of applying a differentelectrical signal to the depot of BAT and delivering a differentchemical to the depot of BAT.

In another embodiment, a medical method can include neuromodulating asympathetic nervous system of a patient proximate to a depot of BAT of apatient so as to activate the BAT and increase energy expenditure of theBAT, and simultaneously with the neuromodulating of the sympatheticnervous system, suppressing a parasympathetic nervous system of thepatient proximate to the depot of brown adipose tissue.

The method can have any number of variations. For example,neuromodulating the sympathetic nervous system can activate sympatheticnerves innervating the BAT, and suppressing the parasympathetic nervoussystem can suppress parasympathetic nerves innervating the BAT. Each ofthe parasympathetic nerves can have a larger diameter than each of thesympathetic nerves. For another example, the suppression of theparasympathetic nervous system begins before the neuromodulation of thesympathetic nervous system so as to start suppressing theparasympathetic nervous system before the sympathetic nervous system isneuromodulated. For still another example, neuromodulating thesympathetic nervous system can include delivering a first chemical tothe patient. Suppressing the parasympathetic nervous system can includeone of delivering a second chemical to the patient that is differentthan the first chemical and applying an electrical signal to thepatient. For yet another example, neuromodulating the sympatheticnervous system can include at least one of applying an electrical signalto the patient, delivering a chemical to the patient, cooling thepatient, and applying a light to the patient.

For another example, neuromodulating the sympathetic nervous system caninclude applying a first electrical signal to the patient. In someembodiments, suppressing the parasympathetic nervous system can includeapplying a second electrical signal to the patient that is differentthan the first electrical signal. The second electrical signal can havea variety of configurations. For example, a current of the firstelectrical signal can be in a range of ten to one hundred times greaterthan a current of the second electrical signal. For another example, thesecond electrical signal can include one of a hyperpolarizing lowerenergy pulse as compared to the first electrical signal, and adepolarizing lower energy pulse as compared to the first electricalsignal. In some embodiments, suppressing the parasympathetic nervoussystem can include applying a chemical to the patient.

In another aspect, a medical apparatus is provided that in oneembodiment includes at least one electrode configured to directlycontact a tissue of a patient proximate to a depot of BAT and tosimultaneously deliver first and second electrical signals to thepatient. The first electrical signal can be configured to causeactivation of a first nerve type in the BAT so as to increase energyexpenditure of the BAT. The second electrical signal can be configuredto inhibit a second nerve type in the BAT that is different from thefirst nerve type. The apparatus can also include at least one signalgenerator in electronic communication with the at least one electrodeand configured to generate the first and second electrical signalsdelivered by the at least one electrode. The apparatus can have anynumber of variations.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a schematic view of an oxidative phosphorylation cycle thatoccurs in mitochondria within BAT cells;

FIG. 2 is a schematic view of BAT mitochondria showing an oxidativephosphorylation cycle that occurs in the mitochondria;

FIG. 3 is a transparent view of a portion of a human neck, chest, andshoulder area with a shaded supraclavicular region; and

FIG. 4 is a schematic view of one embodiment of an implantable devicefor activating BAT.

DETAILED DESCRIPTION OF THE INVENTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment may be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

Various exemplary methods and devices are provided for inhibiting nerveswhen activating brown adipose tissue (BAT). In general, the methods anddevices can facilitate activation of BAT to increase thermogenesis,e.g., increase heat production and energy expenditure in the patient,which over time can lead to one or more of weight loss, a change in themetabolism of the patient, e.g., increasing the patient's basalmetabolic rate, and improvement of comorbidities associated withobesity, e.g., Type II diabetes, high blood pressure, etc. In this way,weight loss, increased metabolic rate, and/or comorbidity improvementcan be induced without performing a major surgical procedure, withoutrelying on administration of one or more pharmaceuticals, withoutrelying on cooling of the patient, and without surgically altering apatient's stomach and/or other digestive organs. A first nerve type(e.g., sympathetic nerves) innervating BAT can be activated while atleast one other nerve type (e.g., parasympathetic nerves and/or sensorynerves) innervating BAT is being suppressed. In general, a firstneuromodulator (e.g., an electrical signal, a chemical, a light,cooling, mechanical manipulation or vibration, a magnetic field, etc.)can be applied to activate the first nerve type, and a secondneuromodulator can be applied to inhibit the at least one other nervetype. In this way, parasympathetic nerves and/or sensory nervesinnervating BAT can be inhibited when activating sympathetic nervesinnervating BAT. The second neuromodulator can be applied before thefirst neuromodulator so as to start inhibiting the at least one othernerve type before the first nerve type begins to be activated by thefirst neuromodulator. Starting the inhibition of the at least one othernerve type before the first nerve type begins to be activated can helpprevent the first neurotransmitter from activating the at least oneother nerve type, e.g., due to an electrical or light signal beingapplied by the first neurotransmitter having sufficient strength toactivate the first nerve type and the at least one other nerve type(absent the at least one other nerve type's prior inhibition). The firstand second neuromodulators can be applied simultaneously, which canfacilitate inhibition of the at least one other nerve type throughoutthe activation of the first nerve type.

Sympathetic nerves innervating BAT can be activated using at least oneneuromodulator (e.g., electrical energy, a light, cooling, a chemical,mechanical manipulation or vibration, a magnetic field, etc.) toincrease energy expenditure, as discussed further below. In rodents,parasympathetic nerves can be found in paravertebral BAT depots, but notin intrascapular BAT depots. In humans, parasympathetic nerves may befound in paravertebral BAT depots and in supraclavicular BAT depots.Parasympathetic nerves (also referred to as craniosacral nerves andcholinergic nerves) of a human's parasympathetic nervous system can alsoinnervate the BAT, and the parasympathetic nerves can be activated bythe neuromodulator that is activating the sympathetic nerves. As will beappreciated by a person skilled in the art, the sympathetic nervoussystem and the parasympathetic nervous system generally functionopposite to one another in complementary fashion. The sympatheticnervous system typically functions in actions requiring quick responses,while the parasympathetic nervous typically functions in actions that donot require immediate reactions. If both of the sympathetic andparasympathetic nervous systems are activated, the parasympatheticnervous system will generally oppose the actions of the sympatheticnervous system. Accordingly, if both sympathetic and parasympatheticnerves are activated when attempting to activate BAT, theparasympathetic nerve activation can attenuate the effects of thesympathetic nerve stimulation. Thus, the advantageous effect(s) that canresult from activating the BAT, e.g., from activating the sympatheticnerves, can be reduced and, in some instances, can be eliminatedentirely due to the parasympathetic nerve activation. Accordingly,activating BAT to activate the sympathetic nerves and inhibiting theparasympathetic nerves can allow the BAT activation to provide theadvantageous effect(s) of BAT activation without being partially orfully suppressed due to parasympathetic nerve activation.

Sensory nerves (e.g., pressure sensitive nerves and temperaturesensitive nerves) can innervate BAT. The sensory nerves can be activatedwhen attempting to activate the BAT, e.g., a temperature change causedby the neuromodulator can trigger temperature sensitive nerves. Theactivation of the sensory nerves can serve in a feedback loop that canattenuate the effects of the stimulation of the sympathetic nerves as anatural defense mechanism attempting to prevent the body from beingharmed by the unexpected activation, the source of which the bodygenerally does not know. Thus, similar to that discussed above regardingparasympathetic nerves, activating the sensory nerves when attempting toactivate the BAT can adversely affect the BAT activation. Accordingly,neuromodulating the sympathetic nerves to activate the BAT whileinhibiting the sensory nerves can allow the BAT activation to providethe advantageous effect(s) of BAT activation without being partially orfully suppressed due to sensory nerve activation.

Parasympathetic and sympathetic nerves form an efferent pathwayincluding preganglionic and postganglionic neurons. Second-orderpostganglionic neurons synapse on smooth and cardiac muscle and alsocontrol glandular secretion. In addition to preganglionic andpostganglionic neurons, control systems of the autonomic nervous system(ANS), which includes the sympathetic and parasympathetic nervoussystems, also involve supraspinal controlling and integrative neuronalcenters; supraspinal, spinal, ganglionic, and peripheral interneurons;and afferent neurons. Afferent neurons have cell bodies in the dorsalroot ganglia or cranial nerve somatic sensory ganglia. Afferent axonstravel in somatic peripheral nerves or along with autonomic efferentnerves.

The parasympathetic preganglionic component of the ANS has a supraspinaland spinal portion. Parasympathetic preganglionic neurons are found infour parasympathetic brain stem nuclei: nucleus Edinger-Westphal,superior salivatory nucleus, inferior salivatory nucleus, and the dorsalvagal complex of the medulla. Their axons exit via cranial nerves 3(oculomotor); 7 (facial nerve); 9 (glossopharyngeal nerve); and 10(vagus nerve) respectively. Parasympathetic preganglionic neurons arealso found in the intermediolateral (IML) cell column of the sacralspinal cord in segments S2-S4 and exit the central nervous system (CNS)via the sacral ventral roots and the spinal nerves and then continue tothe pelvic viscera as the pelvic nerve. The sacral preganglionicparasympathetic efferent axons of the pelvic nerve synapse withpostganglionic parasympathetic neurons in the ganglia of the pelvicplexus. Postganglionic axons innervate the descending colon, rectum,urinary bladder, and sexual organs.

The sympathetic preganglionic component of the ANS is purely spinal.Sympathetic preganglionic neurons (SPNs) are found in the IML cellcolumn of the thoracic and lumbar spinal cord in segments T1-L2 and exitthe CNS via the thoracolumbar ventral roots. The sympathetic segmentaloutflow can vary, and the outflow can start as high as C8 or as low asT2 and end at L1 or L3. The thinly myelinated preganglionic fibers exitvia the ventral roots as the white rami communicantes. Many sympatheticpreganglionic fibers synapse in the paravertebral ganglia, which arepaired and lie next to the spine from the cervical to the sacralsegments. There are three cervical paravertebral ganglia: the superiorcervical ganglion, the middle cervical ganglion, and the stellateganglion. There are usually eleven thoracic ganglia, four lumbarganglia, and four or five sacral ganglia. Sympathetic preganglionicaxons can synapse in paravertebral ganglia at the segment of their exitor can pass up or down several segments of the sympathetic chain beforesynapsing. One sympathetic preganglionic axon will synapse with severalpostganglionic neurons. Postganglionic axons are unmyelinated, smalldiameter fibers that leave the paravertebral ganglia via the gray ramicommunicantes and exit via the segmental spinal nerves.

Some sympathetic preganglionic axons pass through the paravertebralganglia without synapsing and constitute the splanchnic nerves thatinnervate three prevertebral ganglia: celiac ganglion, superiormesenteric ganglion, and inferior mesenteric ganglion (IMG), as well asthe adrenal medulla. Postsynaptic axons from the prevertebral gangliacourse to the abdominal and pelvic viscera as the hypogastric,splanchnic, and mesenteric plexuses.

Sweat glands, piloerector muscles, and most small blood vessels receiveonly sympathetic innervation. Diffuse sympathetic nervous systemdischarge results in pupillary dilatation, increased heart rate andcontractility, bronchodilation, vasoconstriction of the mesentericcirculation, and vasodilation of skeletal muscle arterioles. This is the“fight or flight” defense reaction.

Supraspinal neurons involved in the control systems of the ANS arelocated in the nucleus of the tractus solitarius (NTS), nucleusambiguus, dorsal motor nucleus of vagus, dorsal raphe nucleus, medullaryreticular formation nuclei, locus ceruleus, hypothalamus, limbic system,and the primary sensory and motor cortex. The hypothalamus has uncrossedsympathetic descending pathways to the midbrain, lateral pons, andmedullary reticular formation. Descending reticulospinal pathways fromthe pons and medulla to interneurons in the spinal cord influence theIML cells. The NTS receives afferents from the viscera and functions asan integrating center for reflex activity as well as a relay station tothe hypothalamus and limbic systems.

At the effector organs, sympathetic ganglionic neurons releasenoradrenaline (norepinephrine), along with other cotransmitters such asadenosine triphosphate (ATP), to act on adrenergic receptors, with theexception of the sweat glands and the adrenal medulla. Acetylcholine isthe preganglionic neurotransmitter for both divisions of the ANS, aswell as the postganglionic neurotransmitter of parasympathetic neurons.Nerves that release acetylcholine are said to be cholinergic. In theparasympathetic system, ganglionic neurons use acetylcholine as aneurotransmitter, to stimulate muscarinic receptors. At the adrenalcortex, there is no postsynaptic neuron. Instead, the presynaptic neuronreleases acetylcholine to act on nicotinic receptors. Stimulation of theadrenal medulla releases adrenaline (epinephrine) into the bloodstreamwhich will act on adrenoceptors, producing a widespread increase insympathetic activity. Blocking either the release of acetylcholine fromthese nerves, or blocking the binding of this neurotransmitter to thereceptors on BAT with an anticholinergic agent can help suppressparasympathetic activity, thereby improving the effectiveness of the BATneuromodulation. This blocking can be done locally or globally.

Following a surgical procedure to treat obesity such as Roux-en-Ygastric bypass (RYGB), a patient can lose weight due to an increase inenergy expenditure, as demonstrated in a rodent model for example inStylopoulos et al., “Roux-en-Y Gastric Bypass Enhances EnergyExpenditure And Extends Lifespan In Diet-Induced Obese Rats,” Obesity 17(1 October 2009), 1839-47. Additional data from Stylopoulos et al. (notpublished in the previous article or elsewhere as of the filing date ofthe present application) indicates that RYGB is also associated withincreased levels of uncoupling protein 1 (UCP1), which is an uncouplingprotein in mitochondria of BAT, as well as with a significant reductionin the size of fat stores within BAT and an increased volume of BAT. Itthus appears that RYGB causes activation of BAT, although as discussedabove, surgical procedures to treat obesity, such as gastric bypass,risk if not necessarily cause a variety of undesirable results in atleast some patients. Devices and methods to activate BAT, without amajor surgical procedure like RYGB, to increase energy expenditure aretherefore provided.

One characteristic of BAT that distinguishes it from white adiposetissue (WAT) stores is the high number of mitochondria in a single BATcell. This characteristic makes BAT an excellent resource for burningenergy. Another distinguishing characteristic of BAT is that whenactivated, UCP1 is utilized to introduce inefficiency into the processof adenosine triphosphate (ATP) creation that results in heatgeneration. Upregulation of UCP1 is therefore a marker of BATactivation.

Activation of brown adipocytes leads to mobilization of fat storeswithin these cells themselves. It also increases transport of FFA intothese cells from the extracellular space and bloodstream, particularlywhen the local reserves that are associated with BAT are depleted. FFAsin the blood are derived primarily from fats metabolized and releasedfrom adipocytes in WAT as well as from ingested fats. Stimulation of thesympathetic nervous system is a major means of physiologicallyactivating BAT. Sympathetic nerve stimulation also induces lipolysis inWAT and release of FFA from WAT into the bloodstream to maintain FFAlevels. In this way, sympathetic stimulation leads ultimately to thetransfer of lipids from WAT to BAT followed by oxidation of these lipidsas part of the heat generating capacity of BAT. This activation of brownadipocytes can also lead to improvements in diabetes related markers.

The controlled activation of BAT can be optimized, leading to weightloss, increased metabolic rate, and/or comorbidity improvement, byreducing the stores of triglycerides in WAT. BAT can be activated in avariety of ways. For non-limiting example, a pharmaceutical can beadministered to a patient, the patient can be cooled, the patient can beheated, a magnetic field can be targeted to a region of a patient, aBAT-neuromodulation procedure can be performed on the patient directedto a BAT depot and/or to a nerve innervating BAT, the patient can engagein weight loss therapies, and/or a surgical procedure can be performedon the patient, such as a procedure to induce weight loss and/or toimprove metabolic function, e.g., glucose homeostatis, lipid metabolism,immune function, inflammation/anti-inflammatory balance, etc.Non-limiting examples of a neuromodulation technique configured toactivate a nerve innervating BAT include delivery of a medium to thenerve that induces an action potential in the nerve, e.g., electricity,light, mechanical manipulation or vibration, a magnetic field, achemical, etc. Non-limiting examples of a BAT neuromodulation procedureinclude inducing differentiation of muscle, WAT, preadipocytes, or othercells to BAT, and/or implanting or transplanting BAT cells into apatient. Non-limiting examples of implanting or transplanting BAT cellsinclude removing cells from a patient, culturing the removed cells, andreimplanting the cultured cells; transplanting cells from anotherpatient; implanting cells grown from embryonic stem cells, adult stemcells, or other sources; and genetically, pharmacologically, orphysically altering cells to improve cell function. Non-limitingexamples of such weight loss therapies include a prescribed diet andprescribed exercise. Non-limiting examples of such a surgical procedureinclude gastric bypass, biliopancreatic diversion, a gastrectomy (e.g.,vertical sleeve gastrectomy, etc.), adjustable gastric banding, verticalbanded gastroplasty, intragastric balloon therapy, gastric plication,Magenstrasse and Mill, small bowel transposition, biliary diversion,vagal nerve stimulation, gastrointestinal barrier (e.g., duodenalendoluminal barrier, etc.), and procedures that allow for removal offood from the gastrointestinal tract. Combining one or more treatments,particularly a weight loss therapy or a weight loss surgical procedurewhich does not activate BAT, e.g., a procedure other than RYGB,biliopancreatic diversion (BPD) with or without duodenal switch, or someduodenal or other intestinal barrier (e.g., a prescribed diet and/orexercise program, adjustable gastric banding, vertical bandedgastroplasty, sleeve gastrectomy, gastric plication, Magenstrasse andMill, intragastric balloon therapy, some duodenal or other intestinalbarrier, and small bowel transposition, with a means for acute orchronic activation of BAT such as the neuromodulation discussed herein,can result in desirable patient outcomes through a combined approach.

In some embodiments, exposure to cold temperature can lead to theactivation of BAT to help regulate body temperature. Exemplaryembodiments of using cooling to activate BAT are described in U.S.application Ser. No. 13/977,555 entitled “Methods And Devices ForActivating Brown Adipose Tissue With Cooling” filed Jun. 28, 2013, whichis hereby incorporated by reference in its entirety. In someembodiments, BAT can be activated by being electrically stimulated.Exemplary embodiments of using electrical stimulation to activate BATare described in more detail in U.S. Pat. Pub. No. 2011/0270360 entitled“Methods And Devices For Activating Brown Adipose Tissue UsingElectrical Energy” filed Dec. 29, 2010, which is hereby incorporated byreference in its entirety. In some embodiments, BAT can be activatedusing light. Exemplary embodiments of using light to activate BAT aredescribed in more detail in U.S. Pat. Pub. No. 2014/0088487 entitled“Methods And Devices For Activating Brown Adipose Tissue Using Light”filed Jun. 28, 2013, which is hereby incorporated by reference in itsentirety. In some embodiments, BAT can be chemically activated.Exemplary embodiments of using one or more chemicals to activate BAT aredescribed in more detail in U.S. Pat. Pub. No. 2014/0018767 entitled“Methods And Devices For Activating Brown Adipose Tissue With TargetedSubstance Delivery” filed Jun. 28, 2013, which is hereby incorporated byreference in its entirety. In some embodiments, brown adipocytes can bemodified to increase activation of BAT, e.g., increasing a number of BATadipocytes or increasing activation of BAT by modifying brown adipocytesto express a gene that activates brown adipocytes, such as UCP1.Exemplary embodiments of using modifying brown adipocytes to increaseactivation of BAT are described in more detail in U.S. Pat Pub. No.2014/0199278 entitled “Brown Adipocyte Modification” filed Jun. 28,2013, which is hereby incorporated by reference in its entirety. One ormore techniques to activate BAT can be used at a time, e.g., a patientcan be cooled and electrically stimulated.

A person skilled in the art will appreciate that adult humans havesubstantial BAT depots, as indicated, for example, in J. M. Heaton, “TheDistribution Of Brown Adipose Tissue In The Human,” J Anat., 1972 May,112(Pt 1): 35-39, and W. D. van Marken Lichtenbelt et al,“Cold-Activated Brown Adipose Tissue in Healthy Men,” N. Engl. J. Med.,2009 April, 360, 1500-1508. A person skilled in the art will alsoappreciate that BAT is heavily innervated by the sympathetic nervoussystem, as indicated, for example, in Lever et al., “Demonstration Of ACatecholaminergic Innervation In Human Perirenal Brown Adipose Tissue AtVarious Ages In The Adult,” Anat Rec., 1986 July, 215(3): 251-5, 227-9.Further, “[t]he thin unmyelinated fibers that contain norepinephrine(and not NPY) are those that actually innervate the brown adipocytesthemselves. They form a dense network within the tissue, being incontact with each brown adipocyte (bouton-en-passant), and their releaseof norepinephrine acutely stimulates heat production and chronicallyleads to brown adipose tissue recruitment.” B. Cannon, and J.Nedergaard, “Brown Adipose Tissue: Function And PhysiologicalSignificance,” Physiol Rev., 2004: 84: 277-359.

Nerves innervating BAT can be neuromodulated to activate UCP1 and henceincrease energy expenditure through heat dissipation throughtranscutaneous and/or direct neuromodulation of nerves innervating BAT.Transcutaneous and direct neuromodulation are each discussed below inmore detail.

Because BAT activation may lead to an increase in body temperaturelocally, regionally, or systemically, transcutaneous and/or directneuromodulation of nerves innervating BAT can be combined with one ormore heat dissipation treatments, before and/or after transcutaneousand/or direct neuromodulation of BAT. Non-limiting examples of such aheat dissipation treatment include inducing cutaneous/peripheralvasodilation, e.g., local or systemic administration of Alphaantagonists or blockers, direct thermal cooling, etc.

Whether BAT is activated directly and/or transcutaneously, target areasfor BAT nerve neuromodulation and/or direct neuromodulation of brownadipocytes can include areas proximate to BAT depots, e.g., asupraclavicular region, the nape of the neck, over the scapula,alongside the spinal cord, near proximal branches of the sympatheticnervous system that terminate in BAT depots, and around at least one ofthe kidneys. Any BAT depot can be selected for activation. Fornon-limiting example, in one embodiment illustrated in FIG. 3, a device(not shown) configured to neuromodulate BAT, e.g., using electricity,can be positioned proximate to an area over a scapula in asupraclavicular region S.

Various exemplary embodiments of transcutaneous devices configured toapply an electrical signal or other neuromodulation means to activatenerves are described in more detail in U.S. Pat. Pub. No. 2011/0270360entitled “Methods And Devices For Activating Brown Adipose Tissue UsingElectrical Energy” filed Dec. 29, 2010, U.S. Pat. Pub. No. 2009/0132018filed Nov. 16, 2007 and entitled “Nerve Stimulation Patches And MethodsFor Stimulating Selected Nerves,” U.S. Pat. Pub. No. 2008/0147146 filedDec. 19, 2006 and entitled “Electrode Patch And Method ForNeurostimulation,” U.S. Pat. Pub. No. 2005/0277998 filed Jun. 7, 2005and entitled “System And Method For Nerve Stimulation,” U.S. Pat. Pub.No. 2006/0195153 filed Jan. 31, 2006 and entitled “System And Method ForSelectively Stimulating Different Body Parts,” U.S. Pat. Pub. No.2007/0185541 filed Aug. 2, 2006 and entitled “Conductive Mesh ForNeurostimulation,” U.S. Pat. Pub. No. 2006/0195146 filed Jan. 31, 2006and entitled “System And Method For Selectively Stimulating DifferentBody Parts,” U.S. Pat. Pub. No. 2008/0132962 filed Dec. 1, 2006 andentitled “System And Method For Affecting Gastric Functions,” U.S. Pat.Pub. No. 2008/0147146 filed Dec. 19, 2006 and entitled “Electrode PatchAnd Method For Neurostimulation,” U.S. Pat. Pub. No. 2009/0157149 filedDec. 14, 2007 and entitled “Dermatome Stimulation Devices And Methods,”U.S. Pat. Pub. No. 2009/0149918 filed Dec. 6, 2007 and entitled“Implantable Antenna,” U.S. Pat. Pub. No. 2009/0132018 filed Nov. 16,2007 and entitled “Nerve Stimulation Patches And Methods For StimulatingSelected Nerves,” U.S. Pat. Pub. No. 2010/0161001 filed Dec. 19, 2008and entitled “Optimizing The Stimulus Current In A Surface BasedStimulation Device,” U.S. Pat. Pub. No. 2010/0161005 filed Dec. 19, 2008and entitled “Optimizing Stimulation Therapy Of An External StimulatingDevice Based On Firing Of Action Potential In Target Nerve,” U.S. Pat.Pub. No. 2010/0239648 filed Mar. 20, 2009 and entitled “Self-Locating,Multiple Application, And Multiple Location Medical Patch Systems AndMethods Therefor,” U.S. Pat. Pub. No. 2011/0094773 filed Oct. 26, 2009and entitled “Offset Electrode,” and U.S. Pat. No. 8,812,100 filed May10, 2012 and entitled “A Device And Method For Self-Positioning Of AStimulation Device To Activate Brown Adipose Tissue Depot InSupraclavicular Fossa Region.”

Various exemplary embodiments of devices configured to directly apply asignal to neuromodulate nerves are described in more detail in U.S. Pat.Pub. No. 2011/02700360 entitled “Methods And Devices For ActivatingBrown Adipose Tissue Using Electrical Energy” filed Dec. 29, 2010, U.S.Pat. Pub. No. 2005/0177067 filed Jan. 26, 2005 and entitled “System AndMethod For Urodynamic Evaluation Utilizing Micro-Electronic MechanicalSystem,” U.S. Pat. Pub. No. 2008/0139875 filed Dec. 7, 2006 and entitled“System And Method For Urodynamic Evaluation Utilizing MicroElectro-Mechanical System Technology,” U.S. Pat. Pub. No. 2009/0093858filed Oct. 3, 2007 and entitled “Implantable Pulse Generators AndMethods For Selective Nerve Stimulation,” U.S. Pat. Pub. No.2010/0249677 filed Mar. 26, 2010 and entitled “Piezoelectric StimulationDevice,” U.S. Pat. Pub. No. 2005/0288740 filed Jun. 24, 2004 andentitled, “Low Frequency Transcutaneous Telemetry To Implanted MedicalDevice,” U.S. Pat. No. 7,599,743 filed Jun. 24, 2004 and entitled “LowFrequency Transcutaneous Energy Transfer To Implanted Medical Device,”U.S. Pat. No. 7,599,744 filed Jun. 24, 2004 and entitled “TranscutaneousEnergy Transfer Primary Coil With A High Aspect Ferrite Core,” U.S. Pat.No. 7,191,007 filed Jun. 24, 2004 and entitled “Spatially Decoupled TwinSecondary Coils For Optimizing Transcutaneous Energy Transfer (TET)Power Transfer Characteristics,” and European Pat. Pub. No. 377695published as International Pat. Pub. No. WO1989011701 published Nov. 30,2004 and entitled “Interrogation And Remote Control Device.”

Identification of one or more BAT depots for activation can bedetermined on an individualized patient basis by locating BAT depots ina patient by imaging or scanning the patient using PET-CT imaging,tomography, thermography, MRI, or any other technique, as will beappreciated by a person skilled in the art. Non-radioactive basedimaging techniques can be used to measure changes in blood flowassociated with the activation of BAT within a depot. In one embodiment,a contrast media containing microbes can be used to locate BAT. Thecontrast media can be injected into a patient whose BAT has beenactivated. An energy sources such as low frequency ultrasound can beapplied to the region of interest to cause destruction of bubbles fromthe contrast media. The rate of refill of this space can be quantified.Increased rates of refill can be associated with active BAT depots. Inanother embodiment, a contrast media containing a fluorescent media canbe used to locate BAT. The contrast media can be injected into a patientwhose BAT has been activated. A needle based probe can be placed in theregion of interest that is capable of counting the amount of fluorescentcontrast that passes the probe. Increased counts per unit timecorrespond to increased blood flow and can be associated with activatedBAT depots. Because humans can have a relatively small amount of BAT andbecause it can be difficult to predict where BAT is most prevalent evennear a typical BAT depot such as the nape of the neck, imaging a patientto more accurately pinpoint BAT depots can allow more nerves innervatingBAT to be activated and with greater precision. Any number of BAT depotsidentified through patient imaging can be marked for future referenceusing a permanent or temporary marker. As will be appreciated by aperson skilled in the art, any type of marker can be used to mark a BATdepot, e.g., ink applied on and/or below the epidermis, a dye injection,etc. The marker can be configured to only be visible under speciallighting conditions such as an ultraviolet light, e.g., a black light.

Whether BAT is activated directly and/or transcutaneously, targetcellular areas for BAT nerve activation and/or direct activation ofbrown adipocytes can include cell surface receptors (e.g., TGR5, β₁AR,β₂AR, β₃AR, etc.), nuclear receptors (e.g., PPARγ, FXR, RXR, etc.),transcription co-activators and co-repressors (e.g., PGC1α, etc.),intracellular molecules (e.g., 2-deiodinase, MAP kinase, etc.), UCP1activators, individual cells and related components (e.g., cell surface,mitochondria, and organelles), transport proteins, PKA activity,perilipin and HSL (phospho PKA substrate), CREBP (cAMP responseelement-binding protein), adenosine monophosphate-activated proteinkinase (AMPK), bile acid receptors (e.g., TGR5, FGF15, FXR, RXRα, etc.),muscarinic receptors, etc.

In the course of treating a patient, BAT nerves and/or brown adipocytescan be neuromodulated at any one or more BAT depots directly orindirectly and can be neuromodulated simultaneously, e.g., two or moreBAT depots being concurrently activated, or activated sequentially,e.g., different BAT depots being activated at different times.Simultaneous neuromodulation of BAT can help encourage more and/orfaster energy expenditure. Sequential neuromodulation of BAT can helpprevent the “burning out” of target nerves and can help stimulate thecreation of new BAT cells. Sequential nerve neuromodulation can includeactivating the same BAT depot more than once, with at least one otherBAT depot being activated before activating a previously activated BATdepot. Simultaneous and/or sequential neuromodulation can help preventtachypylaxis.

BAT and the nerves innervating BAT can each be neuromodulatedtranscutaneously (e.g., from outside a patient's body) or directly(e.g., by direct contact therewith). For a subcutaneous example, aneuromodulator can be fully implanted within a patient to be in directcontact with a BAT depot to allow activation of the BAT depot. Foranother subcutaneous example, a neuromodulator can be fully implantedwithin a patient to be in direct contact with a nerve innervating a BATdepot to allow activation of the nerve. For a percutaneous example, aneuromodulator can be partially implanted within a patient to be indirect contact with a BAT depot to allow activation of the BAT depot,e.g., an external skin patch including at least one electrode positionedon a skin surface of a patient with at least one conductor extendingfrom the at least one electrode and through the skin surface to the BATdepot, an external skin patch including at least one electrodepositioned on a skin surface of a patient with at least onelight-emitting fiber optic wire extending from the at least oneelectrode and through the skin surface to the BAT depot, etc. Foranother percutaneous example, a neuromodulator can be partiallyimplanted within a patient to be in direct contact with a nerveinnervating a BAT depot to allow activation of the nerve, e.g., anexternal skin patch including at least one electrode positioned on askin surface of a patient with at least one conductive needle extendingfrom the at least one electrode and through the skin surface to thenerve, an external skin patch including at least one electrodepositioned on a skin surface of a patient with at least onelight-emitting fiber optic wire extending from the at least oneelectrode and through the skin surface to the nerve, etc. For atranscutaneous example, a neuromodulator can be positioned external to apatient proximate a BAT depot to allow activation thereof, e.g., anexternal skin patch including at least one electrode positioned on askin surface of a patient with a conductive gel coupled to the at leastone electrode, etc.

Regardless of whether the BAT or nerves innervating BAT areneuromodulated transcutaneously or directly using one or moreneuromodulation means (e.g., electricity, light, mechanical manipulationor vibration, a magnetic field, a chemical substance, etc.) so as toactivate sympathetic nerves innervating the BAT, at least one othernerve type innervating the BAT can be inhibited, as mentioned above.

In one exemplary embodiment, the BAT can be activated using a firstelectrical signal and a second electrical signal. The first electricalsignal can be configured to stimulate the sympathetic nerves, and thesecond electrical signal can be configured to inhibit the other nervetype, e.g., to inhibit parasympathetic nerves and/or sensory nerves.Both of the first and second electrical signals can be deliveredtranscutaneously, which can facilitate application of the first andsecond electrical signals by allowing the first and second electricalsignals to be delivered using the same device applied transcutaneouslyto a patient. In another embodiment, both of the first and secondelectrical signals can be directly delivered, which can allow forunobtrusive BAT stimulation. In an exemplary embodiment, the secondelectrical signal can begin to be applied to the BAT before the firstelectrical signal is applied to the BAT which can prevent the firstelectrical signal from activating the other nerve type when applied tothe BAT, e.g., due to the first electrical signal having sufficientstrength to activate the sympathetic nerves and the other nerve type(absent the at least one other nerve type's prior inhibition).

FIG. 4 illustrates one exemplary embodiment of an implantable device 100configured to generate and deliver an electrical signal to tissue suchas BAT. The implantable device 100 can be fully implanted within apatient's body, or the device 100 can be only partially implanted withina patient's body (e.g., be percutaneous) so as to be at least partiallylocated outside the patient's body. The implantable device 100 caninclude a housing 102 coupled to a suitable power source or battery 104such as a lithium battery, a first waveform generator 106, and a secondwaveform generator 110. As in the illustrated embodiment, the battery104 and the first and second waveform generators 106, 110 can be locatedwithin the housing 102. In another embodiment, a battery can be externalto a housing and be wired or wirelessly coupled thereto. The housing 102is preferably made of a biocompatible material. The first and secondwaveform generators 106, 110 can be electrically coupled to and poweredby the battery 104. The waveform generators 106, 110 can be of anysuitable type, such as those sold by Texas Instruments of Dallas, Tex.under model number NE555. The first waveform generator 106 can beconfigured to generate a first waveform or low frequency modulatingsignal 108, and the second waveform generator 110 can be configured togenerate a second waveform or carrier signal 112 having a higherfrequency than the first waveform 108. The carrier signal 112 can makeit easier to stimulate BAT and/or nerves innervating BAT by using lessenergy, and/or can make the electrical signal more comfortable for thepatient. The first waveform 108 cannot easily, in and of themselves,pass through body tissue to effectively stimulate target nerves. Thesecond waveform 112 can, however, help the electrical signal penetratethrough body tissue. The second waveform 112 can be applied along withthe first waveform 108 to an amplitude modulator 114, such as themodulator having the designation On-Semi MC 1496, which is sold by TexasInstruments.

The modulator 114 can be configured to generate a first modulatedwaveform 116 that is transmitted through a lead 118 to one or moreelectrodes 120. Four electrodes are illustrated, but the device 100 caninclude any number of electrodes having any size and shape. The lead 118can be flexible, as in the illustrated embodiment. The electrodes 120can be configured to, in turn, apply the first modulated waveform 116 toa first target nerve 122 to stimulate the target nerve 122. The firstwaveform 108 can be a square wave, and the second waveform 112 can be asinusoidal signal. The first modulated waveform 116, e.g., the first andsecond waveforms 108, 112, can define the first electrical signal, e.g.,the signal configured to stimulate sympathetic nerves.

The modulator 114 can be configured to generate a second modulatedwaveform 124 that is transmitted through the lead 118 to one or more ofthe electrodes 120 to apply the second modulated waveform 124 to asecond target nerve (not shown) near the first target nerve 122. Thesecond modulated waveform 124 can define the second electrical signal,e.g., the signal configured to stimulate parasympathetic nerves and/orsensory nerves.

The modulator 114 can be configured to execute a first algorithm togenerate the first modulated waveform 116 and can be configured toexecute a second algorithm to generate the second modulated waveform124. The first and second algorithms can be stored in a memory of themodulator 114, e.g., in a memory of the modulator as a microcontrolleror other type of processor such as a central processing unit (CPU).

The first and second modulated waveforms 116, 124 each include amodulating signal and a carrier signal in this illustrated embodiment,but a device similar to the device 100 can be configured to similarlygenerate a single first signal and a single second signal thatrespectively define the first and second electrical signals. In otherwords, the first and second electrical signals can each include a singlesignal, e.g., lack a carrier signal.

The first electrical signal, whether transcutaneously or directlydelivered, can be configured in a variety of ways. In an exemplaryembodiment, the first electrical signal directly delivered to BAT canhave a voltage having an amplitude in a range of about 1 to 20 V, e.g.,about 10 V, e.g., about 4 V, about 7 V, etc.; a current having anamplitude in a range of about 2 to 6 mA, e.g., about 3 mA; a pulse widthin a range about 10 μs to 1 ms, e.g., about 0.1 ms, about 1 ms, about0.4 ms, etc.; an activation signal pulse frequency in a range of about0.1 to 40 Hz, e.g., about 10 Hz or in a range of about 1 to 20 Hz; and aduration of signal train in a range of about 1 second to continuous,e.g., about 30 seconds, etc. Specific parameters for the firstelectrical signal can be different based on where the first electricalsignal is delivered, e.g., based on whether an electrode delivering thefirst electrical signal is transcutaneously placed or is implanted. Inan exemplary embodiment of direct and/or subcutaneous stimulation ofmyelinated fibers, the first electrical signal can have a currentamplitude in a range of about 0.1 to 10 mA and a pulse width in a rangeof about 50 to 300 μsec. In general, a charge needed to stimulatemyelinated fibers is less than a charge needed to stimulate unmyelinatedfibers. In an exemplary embodiment of direct and/or subcutaneousstimulation of unmyelinated fibers, the first electrical signal can havea current amplitude greater than and a pulse width at least as high aswhen applied to myelinated fibers, e.g., the first electrical signalhaving a current amplitude of greater than 10 mA and a pulse width of atleast 300 μsec (e.g., a pulse width in a range of about 300 to 1000μsec). In an exemplary embodiment of transcutaneous stimulation ofmyelinated fibers, the first electrical signal can have a currentamplitude of at least about 10 mA (e.g., in a range of about 10 to 100mA) and a pulse width less than about 400 μsec. In general, currentamplitudes above 100 mA can be uncomfortable for a patient. In anexemplary embodiment of transcutaneous stimulation of unmyelinatedfibers, the first electrical signal can have a current amplitude of atleast about 50 mA (e.g., in a range of about 50 to 100 mA) and a pulsewidth in a range of about 400 to 1000 μsec. As will be appreciated by aperson skilled in the art, the charge used to stimulate fibers can beadjusted by adjusting the current amplitude and the pulse width toachieve a desired charge. In general, in adjusting the charge, reducingthe pulse width for the first electrical signal can be beneficial overincreasing the pulse width since very long pulse widths could causedamage and/or discomfort to the patient. A person skilled in the artwill appreciate that a specific parameter may not have a precisenumerical value but nevertheless be considered to be “about” thatspecific numerical value due to one or more factors, such asmanufacturing tolerances of a device that generates a signal having thespecific parameter.

A time between start of signal trains for a noncontinuous electricalsignal delivered to BAT can be of any regular, predictable duration,e.g., hourly, daily, coordinated around circadian, ultradian, or othercycles of interest, etc., such as about ten minutes or about ninetyminutes, or can be of any irregular, unpredictable duration, e.g., inresponse to one or more predetermined trigger events. In general,predetermined trigger events include events that are sensed by orotherwise signaled to the device. Non-limiting examples of triggerevents include the patient eating, the patient resting (e.g., sleeping),a threshold temperature of the patient (e.g., a temperature in theneuromodulated BAT depot or a core temperature), a directionalorientation of the patient (e.g., recumbent as common when sleeping), achange in the patient's weight, a change in the patient's tissueimpedance, manual activation by the patient or other human (e.g., via anonboard controller, via a wired or wirelessly connected controller, orupon skin contact), a blood chemistry change in the patient (e.g., ahormonal change), low energy expenditure, menstrual cycles in women,medication intake (e.g., an appetite suppressant such as topiramate,fenfluramine, etc.), an ultradian or other circadian rhythm of thepatient, and a manually-generated or automatically-generated signal froma controller in electronic communication, wired and/or wireless, withthe device. In one embodiment, the patient eating can be determinedthrough a detection of heart rate variability, as discussed in moredetail in U.S. Pat. No. 8,696,616 filed on Dec. 29, 2010 entitled“Obesity Therapy And Heart Rate Variability” and U.S. Pat. Pub. No.2012/0172783 filed on Dec. 29, 2010 and entitled “Obesity Therapy AndHeart Rate Variability,” which are hereby incorporated by reference intheir entireties.

A length of time for a continuously delivered BAT signal can vary. Tomore accurately simulate a weight loss surgery that has a continuous orchronic effect on a patient for an extended period of time, the firstelectrical signal can be continuously or chronically delivered for anextended, and preferably predetermined, amount of time. In an exemplaryembodiment, the predetermined amount of time can be at least one day,e.g., in a range of one day to at least four weeks, at least one week,at least four weeks, etc. Various exemplary embodiments of the firstelectrical signal that can be delivered to stimulate BAT are furtherdescribed in, for example, previously mentioned U.S. Pat. Pub. No.2011/0270360 entitled “Methods And Devices For Activating Brown AdiposeTissue Using Electrical Energy” filed Dec. 29, 2010.

The second electrical signal, whether transcutaneously or directlydelivered, can be configured in a variety of ways. In an exemplaryembodiment, the second electrical signal can be different than the firstelectrical signal in one or more ways, e.g., have a different voltage, adifferent current, a different amplitude, a different pulse width, adifferent polarity, etc. In this way, the first electrical signal can betargeted to a first nerve type, e.g., sympathetic nerves, by having afirst configuration, and the second electrical signal can be targeted toa second, different nerve type, e.g., parasympathetic nerves and/orsensory nerves, by having a second configuration that is different thanthe first configuration.

The second electrical signal being different than the first electricalsignal can allow the second electrical signal to target parasympatheticnerves using fiber diameter selectivity. In other words, the secondelectrical signal can be configured to activate nerve fibers having afirst diameter without activating nerve fibers having diametersdifferent than the first diameter. As discussed above, sympatheticnerves include postganglionic unmyelinated, small diameter fibers, whileparasympathetic nerves include preganglionic myelinated, larger diameterfibers. The second electrical signal can thus be configured to targetand activate the preganglionic myelinated, larger diameter fiberswithout activating the postganglionic unmyelinated, small diameterfibers. The energy required to activate the postganglionic unmyelinated,small diameter fibers (e.g., the sympathetic nerves) is greater than theenergy required to activate the preganglionic myelinated, largerdiameter fibers (e.g., the parasympathetic nerves). The relativeenergies of the first and second electrical signals can allow the lowerenergy second electrical signal to suppress the parasympathetic fiberswithout activating the sympathetic nerves. After suppression of theparasympathetic fibers, the higher energy first electrical signal canactivate the sympathetic fibers without activating the suppressedparasympathetic nerves.

Signal characteristics of the first and second electrical signals can becontrolled to facilitate the targeting of nerves using fiber diameterselectivity. Threshold differences between the first and secondelectrical signals can be controlled by varying signal characteristicsof the first and second electrical signals, such as pulse width anddelay between first and second pulses of a biphasic waveform.

In an exemplary embodiment, the second electrical signal can bedifferent than the first electrical signal by having less energy thanthe first electrical signal. For example, a current of the firstelectrical signal can be greater than a current of the second electricalsignal. Sympathetic nerves are postganglionic, and postganglionic fibersare unmyelinated and generally have a small diameter. Conversely,parasympathetic nerves and sensory nerves are pre-ganglionic and aremyelinated and generally have a larger diameter than sympathetic nerves.The second electrical signal having a current less than the firstelectrical signal's current can facilitate the second electricalsignal's suppression of the myelinated nerves before the firstelectrical signal begins to be applied and can facilitate the secondelectrical signal's suppression of the myelinated nerves while the firstelectrical signal also being applied stimulates the unmyelinated nerves.The second electrical signal can be applied before the first electricalsignal is applied, thereby preventing new action potential formation atthe parasympathetic nerves such that the first electrical signalsubsequently applied cannot activate the parasympathetic nerves. In anexemplary embodiment, the first electrical signal's current can be in arange of ten to one hundred times greater than a current of the secondelectrical signal, which can help ensure that the first electricalsignal targets the first nerve type and the second electrical signaltargets the second nerve type. For example, the second electrical signalcan have a current in a range of about 0.1 mA to 5 mA, and the firstelectrical signal can have a current in a range of ten to one hundredtimes greater than the second electrical signal. For another example,the second electrical signal can have a pulse width that is equal to orless than a pulse width of the first electrical signal, such as by thesecond electrical signal having a pulse width in a range of about 10 μsto 400 μs, and the first electrical signal having a pulse width in arange of about 400 μs to 1000 μs. In an exemplary embodiment, the secondelectrical signal has a pulse width that is less than a pulse width ofthe first electrical signal.

For another example of the second electrical signal having less energythan the first electrical signal, the second electrical signal caninclude a hyperpolarizing lower energy pulse (e.g., an anodic signal) ascompared to the first electrical signal. The hyperpolarizing lowerenergy pulse of the second electrical signal can facilitate inhibitionof the second nerve type while the first electrical signal stimulatesthe first nerve type. The hyperpolarizing lower energy pulse of thesecond electrical signal can be configured to inactivate sodiumchannels, thereby preventing new action potential formation. The secondelectrical signal including the hyperpolarizing lower energy pulse canbe applied to BAT before the first electrical signal is applied to theBAT, thereby preventing new action potential formation at theparasympathetic nerves such that the first electrical signalsubsequently applied to the BAT cannot activate the parasympatheticnerves. The first and second electrical signals can be alternatelyapplied, thereby helping to ensure that the parasympathetic nerveshaving the hyperpolarizing lower energy pulse applied thereto are notactivated in response to application of the first electrical signal.

For another example of the second electrical signal having less energythan the first electrical signal, the second electrical signal caninclude a depolarizing lower energy pulse (e.g., a cathodic stimulus) ascompared to the first electrical signal. The depolarizing lower energypulse of the second electrical signal can facilitate inhibition of thesecond nerve type while the first electrical signal stimulates the firstnerve type. The depolarizing lower energy pulse of the second electricalsignal can be configured to depolarize parasympathetic nerves withoutactivating the parasympathetic nerves (e.g., be lower than that neededto cause activation of the parasympathetic nervous system) such that nonew action potential can be elicited from the parasympathetic nerves.The second electrical signal including the depolarizing lower energypulse can be applied to BAT before the first electrical signal isapplied to the BAT, thereby depolarizing the parasympathetic nerves suchthat the first electrical signal subsequently applied to the BAT cannotactivate the parasympathetic nerves. The first and second electricalsignals can be alternately applied, thereby helping to ensure that theparasympathetic nerves having the depolarizing lower energy pulseapplied thereto are not activated in response to application of thefirst electrical signal.

In another exemplary embodiment of activating a first nerve typeinnervating BAT and inhibiting a second nerve type innervating BAT, theBAT can be neuromodulated using an electrical signal and a chemical. Forexample, the electrical signal can target the first nerve type, and thechemical can target the second nerve type. For another example, thechemical can target the first nerve type, and the electrical signal cantarget the second nerve type.

In one exemplary embodiment, the electrical signal can target the firstnerve type, and a chemical in the form of an anticholinergic agent(e.g., atropine, etc.) can target the second nerve type. Ananticholinergic agent is, generally, a substance that blocks theneurotransmitter acetylcholine in the central and the peripheral nervoussystem, which as discussed above can help suppress parasympatheticactivity and thereby improve the effectiveness of the BATneuromodulation. Anticholinergics are a class of medications thatinhibit parasympathetic nerve impulses by selectively blocking thebinding of the neurotransmitter acetylcholine to its receptor in nervecells. The Anticholinergics are divided into three categories inaccordance with their specific targets in the central and/or peripheralnervous system: antimuscarinic agents, ganglionic blockers, andneuromuscular blockers.

In another exemplary embodiment, the electrical signal can target thefirst nerve type, and a chemical in the form of a depolarization agentcan target the second nerve type. Thus, similar to that discussed aboveregarding the second electrical signal including a depolarizing lowerenergy pulse, the depolarization agent can facilitate inhibition of thesecond nerve type while the electrical signal stimulates the first nervetype.

In still another exemplary embodiment, the electrical signal can targetthe first nerve type, and a chemical in the form of a hyperpolarizationagent can target the second nerve type. Thus, similar to that discussedabove regarding the second electrical signal including a hyperpolarizinglower energy pulse, the hyperpolarization agent can facilitateinhibition of the second nerve type while the electrical signalstimulates the first nerve type.

In yet another exemplary embodiment, the electrical signal can targetthe first nerve type, and a chemical can be configured to target thesecond nerve type by targeting a temperature-sensitive nature of thesecond nerve type. In other words, the second nerve type can includesensory nerves sensitive to temperature, and the chemical can beconfigured to suppress the sensory nerves by affecting a temperature ofthe sensory nerves.

In another exemplary embodiment of activating a first nerve typeinnervating BAT and inhibiting a second nerve type innervating BAT, theBAT can be neuromodulated using a first chemical and a second chemical.The first chemical can be configured to stimulate the sympatheticnerves, and the second chemical can be configured to inhibit the othernerve type, e.g., to inhibit parasympathetic nerves and/or sensorynerves. In an exemplary embodiment, the second chemical can be differentthan the first chemical, thereby facilitating the targeting of differentnerve types by the first and second chemicals.

In another exemplary embodiment of activating a first nerve typeinnervating BAT and inhibiting a second nerve type innervating BAT, thefirst nerve type can be stimulated using at least one of an electricalsignal, a chemical, cooling, and a light, and the second nerve type canbe stimulated using at least one of a different electrical signal and adifferent chemical.

The devices discussed herein can be designed to be disposed of after asingle use, or they can be designed to be used multiple times. In eithercase, however, the device can be reconditioned for reuse after at leastone use. Reconditioning can include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces, and subsequent reassembly. In particular, the devicecan be disassembled, and any number of the particular pieces or parts ofthe device can be selectively replaced or removed in any combination.Upon cleaning and/or replacement of particular parts, the device can bereassembled for subsequent use either at a reconditioning facility, orby a surgical team immediately prior to a surgical procedure. Thoseskilled in the art will appreciate that reconditioning of a device canutilize a variety of techniques for disassembly, cleaning/replacement,and reassembly. Use of such techniques, and the resulting reconditioneddevice, are all within the scope of the present application.

Preferably, the invention described herein will be processed before use.First, a new or used instrument is obtained and if necessary cleaned.The instrument can then be sterilized. In one sterilization technique,the instrument is placed in a closed and sealed container, such as aplastic or TYVEK bag. The container and instrument are then placed in afield of radiation that can penetrate the container, such as gammaradiation, x-rays, or high-energy electrons. The radiation killsbacteria on the instrument and in the container. The sterilizedinstrument can then be stored in the sterile container. The sealedcontainer keeps the instrument sterile until it is opened in the medicalfacility.

It is preferred that device is sterilized. This can be done by anynumber of ways known to those skilled in the art including beta or gammaradiation, ethylene oxide, steam, and a liquid bath (e.g., cold soak).An exemplary embodiment of sterilizing a device including internalcircuitry is described in more detail in U.S. Pat. Pub. No. 2009/0202387filed Feb. 8, 2008 and entitled “System And Method Of Sterilizing AnImplantable Medical Device.” It is preferred that device, if implanted,is hermetically sealed. This can be done by any number of ways known tothose skilled in the art.

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. Allpublications and references cited herein are expressly incorporatedherein by reference in their entirety.

What is claimed is:
 1. A medical method, comprising: stimulating brownadipose tissue of a patient such that first nerves of a first type ofnerves of the patient are activated and second nerves of a second typeof nerves of the patient are suppressed, wherein the second nerves eachhave a diameter that is larger than a diameter of each of the firstnerves.
 2. The method of claim 1, wherein the first type of nerves issympathetic nerves, and second type of nerves is parasympathetic nerves.3. The method of claim 1, wherein the first type of nerves issympathetic nerves, and the second type of nerves is sensory nerves. 4.The method of claim 1, wherein the stimulating includes applying a firstneuromodulator to the brown adipose tissue for activating the firstnerves and applying a second neuromodulator to the brown adipose tissuefor suppressing the second nerves.
 5. The method of claim 4, whereinapplying the first neuromodulator includes delivering a first electricalsignal to the brown adipose tissue; and applying the secondneuromodulator includes delivering a second electrical signal to thebrown adipose tissue that is different than the first electrical signal.6. The method of claim 4, wherein applying the first neuromodulatorincludes applying a light to the brown adipose tissue; and applying thesecond neuromodulator includes applying a different light to the brownadipose tissue.
 7. The method of claim 4, wherein applying the firstneuromodulator includes delivering a chemical to the brown adiposetissue; and applying the second neuromodulator includes delivering adifferent chemical to the brown adipose tissue.
 8. The method of claim4, wherein the application of the second neuromodulator is simultaneouswith the application of the first neuromodulator.
 9. The method of claim8, wherein the application of the second neuromodulator begins beforethe application of the first neuromodulator.
 10. A medical method,comprising: delivering an electrical signal to brown adipose tissue of apatient such that first nerve fibers having a first diameter areactivated and nerve fibers having diameters different than the firstdiameter are not activated.
 11. The method of claim 10, wherein thefirst nerve fibers are fibers of sympathetic nerves, and the nervefibers having different diameters are fibers of parasympathetic nerves.12. The method of claim 10, wherein the first nerve fibers are fibers ofsympathetic nerves, and the nerve fibers having different diameters arefibers of sensory nerves.
 13. The method of claim 10, wherein the firstnerve fibers are postganglionic unmyelinated fibers, and the nervefibers having different diameters are preganglionic myelinated fibers.14. The method of claim 10, wherein the electrical signal includes afirst electrical signal and a second electrical signal that is differentthan the first electrical signal.
 15. The method of claim 9, wherein thesecond electrical signal has less energy than the first electricalsignal by having less current than the first electrical signal, and acurrent of the first electrical signal is in a range of ten to onehundred times greater than a current of the second electrical signal.16. The method of claim 9, wherein the second electrical signal has lessenergy than the first electrical signal by including a hyperpolarizinglower energy pulse as compared to the first electrical signal, or byincluding a depolarizing lower energy pulse as compared to the firstelectrical signal.
 17. The method of claim 9, wherein the secondelectrical signal is delivered to the brown adipose tissue via at leastone electrode before the first electrical signal begins being deliveredto the brown adipose tissue via the at least one electrodesimultaneously with the delivery of the second electrical signal. 18.The method of claim 17, wherein a signal generator begins generating thesecond electrical signal before beginning to generate the firstelectrical signal.
 19. A medical apparatus, comprising: a signalgenerator configured to generate an electrical signal; and an electrodeconfigured to be attached to a patient in contact with brown adiposetissue of the patient and to deliver the generated electrical signal tothe brown adipose tissue such that first nerve fibers having a firstdiameter are activated and such that nerve fibers having diametersdifferent than the first diameter are not activated.
 20. The apparatusof claim 19, wherein the electrical signal includes a first electricalsignal and a second electrical signal that is different than the firstelectrical signal; the first electrical signal is configured to activatethe first nerve fibers; the second electrical signal is configured tosuppress the nerve fibers having diameters different than the firstdiameter; and the first nerve fibers are fibers of sympathetic nerves,and the nerve fibers having different diameters are at least one offibers of parasympathetic nerves and fibers of sensory nerves.